Loss of FOCAD, operating via the SKI messenger RNA surveillance pathway, causes a pediatric syndrome with liver cirrhosis

Ricardo Moreno Traspas, Tze Shin Teoh, Pui-Mun Wong, Michael Maier, Crystal Y Chia, Kenneth Lay, Nur Ain Ali, Austin Larson, Fuad Al Mutairi, Nouriya Abbas Al-Sannaa, Eissa Ali Faqeih, Majid Alfadhel, Huma Arshad Cheema, Juliette Dupont, Stéphane Bézieau, Bertrand Isidor, Dorrain Yanwen Low, Yulan Wang, Grace Tan, Poh San LaiHugues Piloquet, Madeleine Joubert, Hulya Kayserili, Kimberly A Kripps, Shareef A Nahas, Eric P Wartchow, Mikako Warren, Gandham SriLakshmi Bhavani, Majed Dasouki, Renata Sandoval, Elisa Carvalho, Luiza Ramos, Gilda Porta, Bin Wu, Harsha Prasada Lashkari, Badr AlSaleem, Raeda M BaAbbad, Anabela Natália Abreu Ferrão, Vasiliki Karageorgou, Natalia Ordonez-Herrera, Suliman Khan, Peter Bauer, Benjamin Cogne, Aida M Bertoli-Avella, Marie Vincent, Katta Mohan Girisha

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


Cirrhosis is usually a late-onset and life-threatening disease characterized by fibrotic scarring and inflammation that disrupts liver architecture and function. While it is typically the result of alcoholism or hepatitis viral infection in adults, its etiology in infants is much less understood. In this study, we report 14 children from ten unrelated families presenting with a syndromic form of pediatric liver cirrhosis. By genome/exome sequencing, we found recessive variants in FOCAD segregating with the disease. Zebrafish lacking focad phenocopied the human disease, revealing a signature of altered messenger RNA (mRNA) degradation processes in the liver. Using patient's primary cells and CRISPR-Cas9-mediated inactivation in human hepatic cell lines, we found that FOCAD deficiency compromises the SKI mRNA surveillance pathway by reducing the levels of the RNA helicase SKIC2 and its cofactor SKIC3. FOCAD knockout hepatocytes exhibited lowered albumin expression and signs of persistent injury accompanied by CCL2 overproduction. Our results reveal the importance of FOCAD in maintaining liver homeostasis and disclose a possible therapeutic intervention point via inhibition of the CCL2/CCR2 signaling axis.
Original languageEnglish (US)
Pages (from-to)1214-1226
Number of pages13
JournalNature Genetics
Issue number8
StatePublished - Jul 21 2022
Externally publishedYes

Bibliographical note

KAUST Repository Item: Exported on 2022-12-12
Acknowledgements: We are grateful to the families of affected individuals for their participation and kind cooperation in this study. We are also grateful to all members of the Reversade laboratory for constructive discussions and suggestions. We thank R. Weber (Hannover Medical School, Germany) for providing the FOCAD expression construct used for our transient transfections, as well as A. van Hoof (University of Texas Health Science Center at Houston, Texas, USA) and J. Mendell (University of Texas Southwestern Medical Center, Texas, USA) for their insights on the biology of the SKI complex. M.M. was supported by a Career Development Award (CDF Project NR C210812055) from the A*STAR, Biomedical Research Council (Singapore). K.M.G. was supported by the Clinical Research Center grant (IA/CRC/20/1/600002) from India Alliance (India). The authors also thank the King Fahad Medical City Research Center (Saudi Arabia) for the partial support to E.A.F. (grant no. 019-052). B.R. is a fellow of the Branco Weiss Foundation (Switzerland) and the National Research Foundation (Singapore), and an A*STAR and EMBO Young Investigator. This work was also supported by an inaugural Use-Inspired Basic Research (UIBR) central fund and a Brain-Body Initiative (BBI) grant in Neurometabolism to B.R. from the Agency for Science, Technology and Research (A*STAR) in Singapore.

ASJC Scopus subject areas

  • Genetics


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